The intravenous or intramuscular injection of sterile solutions of an iron dextran complex is clinically indicated for the treatment of patients with documented iron deficiency in whom oral administration is unsatisfactory or impossible.
Iron dextran is absorbed from the injection site after intramuscular injection, for example, into the capillaries and the lymphatic system. Circulating iron dextran is cleared from the plasma by cells of the reticuloendothelial system, which split the complex into its components of iron and dextran. IMFERON.RTM., for example, a product previously marketed by Fisons Pharmaceuticals, is released to the blood after uptake by the phagocytic activity of macrophages. See Henderson, et al., Blood 34:357-375 (1969). The iron immediately is bound to available protein moieties to form hemosiderin or ferritin, the physiological forms of iron or, to a lesser extent, to transferrin. This iron, which is subject to physiological control, replenishes the iron component of hemoglobin and other depleted iron stores.
The major benefit of the clinical use of iron dextran is that, due to its large molecular weight (i.e., greater than 70,000 daltons), the iron dextran complex is not excreted by the kidneys. Therefore almost the entire dose of iron dextran remains bioavailable as the iron dextran is metabolized in the liver. The major portion of an intramuscular injection of iron dextran is absorbed within 72 hours. Most of the remaining iron is absorbed over the ensuing 3 to 4 weeks.
Iron dextran for parenteral administration currently is marketed by Steris Pharmaceuticals, Inc. under the brand name INFeD.RTM.. As formulated, this product is a dark brown and slightly viscous sterile liquid complex of ferric oxyhydroxide, beta-FeO(OH), and is a low molecular weight dextran derivative in approximately 0.9% weight per volume sodium chloride for intravenous or intramuscular use. It contains the equivalent of 50 mg of elemental iron (as an iron dextran complex) per ml. Sodium chloride may be added for tonicity. The pH of the solution is between 5.2 and 6.5.
Under electron microscopy, IMFERON.RTM. has been shown to have an inner electron-dense FeO(OH) core with a diameter of approximately 3 nm and an outer moldable plastic dextran shell with a diameter of approximately 13 nm. Almost all of the iron, about 98-99% is present as a stable ferric-dextran complex. The remaining iron represents a very weak ferrous complex.
The dextran component of conventional iron dextran products is a polyglucose that either is metabolized or excreted. Negligible amounts of iron are lost via the urinary or alimentary pathways after administration of iron dextran. Staining from inadvertent deposition of iron dextran in subcutaneous and cutaneous tissues usually resolves or fades within several weeks or months. Various studies have reported that the half life of iron dextran in iron deficient subjects ranges from 5 to more than 20 hours. Notably, these half-life values do not represent clearance of iron from the body because iron is not readily eliminated from the body. See, for example, the package inserts for IMFERON.RTM. and INFeD.RTM., or Hamstra, et al. JAMA 243:1726-1731 (1980).
U.S. Pat. No. 2,820,740 and its reissue RE 24,642 to London et al. describe colloidal injectable iron preparations suitable for parenteral injection formed of a nonionic ferric hydroxide, partially depolymerized dextran complex. Current commercial iron dextran products, based on these two prior patents do not have sufficient purity (see FIGS. 1 and 2) and needed thermal stability (see FIGS. 3 and 4) to safeguard safety and sterility concerns. Also, these commercial products have a relatively short plasma residence time which could cause a potential risk of iron overload in specific organs. See, Carthew, R. E. , et al. Hepatology 13 (3) :534-538 (1991); Pitts, T. O., et al. Nephron 22:316 (1978); Weintraub, L. R., et al. Brit. J. Hematology 59:321 (1985); and Fletcher, L. M., et al., Gastroenterology 97:1011 (1989).
Similarly, U.S. Pat. No. 2,885,393 to Herb also discloses iron dextran complexes. The most suitable range in molecular weight of the partially depolymerized dextran for injection was found to be 30,000 to 80,000 daltons or lower. A subsequent patent to Herb, U.S. Pat. No. 4,180,567, discloses other iron preparations and methods for making and administering such preparations; however, the method disclosed does not teach the heating of iron dextran complexes above 100.degree. C.
Other methods for the production of iron dextran complexes have been described, for example, in U.S. Pat. No. 4,599,405 to Muller et al. regarding iron (III) hydroxy/dextran complexes that are produced using an alkali carbonate, ammonium carbonate or a carbonate of an organic base added to an acid solution containing a partially depolymerized dextran and an iron (III) salt. Thereafter, an alkali metal hydroxide or ammonium hydroxide is added. The suspension so formed is then converted into a solution by heating, and the solution worked up in a known manner.
Alternatively, ferric chloride and dextran can be reacted in aqueous solution in the presence of citric acid as disclosed in U.S. Pat. No. 3,697,502 or by treating reactive trivalent iron with a complex-forming agent consisting of sorbitol, gluconic acid and certain oligosaccharides, in particular proportions and amounts as taught in U.S. Pat. No. 3,686,397.
U.S. Pat. No. 4,749,695 and its divisional, U.S. Pat. No. 4,927,756, both to Schwengers, disclose a water-soluble iron dextran and a process for its manufacture. As disclosed, the dextran utilized has an average molar mass of from 2,000 to 4,000 daltons. Another alternative includes the complexation of ferric hydroxide with hexonic acid derivatives of dextran as in U.S. Pat. No. 4,788,281 to Tosoni.
U.S. Pat. No. 3,908,004 to Kitching discloses the preparation of iron compositions to treat iron-deficiency anemia. Methods of formulating these compositions include the heating of an aqueous alkaline solution of a polysaccharide with a water soluble inorganic iron compound such as ferric oxychloride. The presence of the alkali is said to be necessary to bring about the formation of the complex. However, the alkaline conditions also cause some degradation of the polysaccharide and the low molecular-weight species so formed produce iron compounds which are responsible for undesirable effects.
U.S. Pat. No. 4,659,697 to Tanaka discloses a process for producing an organoiron (II) compound-containing antianemic composition which through the cultivation of a yeast in a saccharide-containing nutrient medium, such as grape juice, in the presence of an iron compound to form a cultured broth comprising an organoiron(II) compound, alcohol and water and removing the alcohol from the cultured broth to an extent that the resulting cultured broth has an alcohol content of less than about 1% by volume, and an antianemic composition produced thereby. The antianemic composition was said to be very stable, with excellent absorbability into a living body and incorporation of iron into hemoglobin.
Iron dextran complexes also have application as imaging agents. For example, dextran/magnetite is disclosed as a particulate solution specifically noted to be stabilized by polymeric dextran. (See Hasegawa et al., U.S. Pat. No. 4,101,435. Several others have used dextrans of various molecular weights as ingredients in the synthesis of magnetic colloids or particles. (See Hasegawa et al., U.S. Pat. No. 4,101,435; Molday, U.S. Pat. No. 4,454,773; and Schroder, U.S. Pat. No. 4,505,726. The resulting complexes of dextran and iron oxide have varying sizes and structures, but all have molecular weights of at least about 500,000 daltons.
The incorporation of high molecular weight dextran into magnetic particles or colloids may, however, cause some patients to experience adverse reactions to the dextran, particularly when such complexes are administered as parenteral magnetic resonance contrast agents. These adverse reactions may also be due in part to problems of high molecular weight polymers such as dextran dissociating from the metal oxide colloid upon prolonged storage or under high temperatures, thereby leaving the metal oxide free to aggregate.
Despite the variety of iron dextran formulations described in the prior act, current iron deficiency products are based on technology that has not satisfactorily resolved stability and purity concerns. What is needed in the therapeutic field of iron supplementation, is an improved next-generation iron dextran product with enhanced purity and thermal stability, as well as prolonged plasma residence time to minimize possible iron overload complications without compromising the efficacy of iron dextran therapy.